The present invention relates to hydantoin compounds, pharmaceutical compositions containing them, and methods of using such compounds in treating inflammatory or immune disease.
Cells adhere to other cells and to substrates through specific, regulated processes that are critical to various biological functions. The proper functioning of the immune system, for example, is dependent upon adhesive interactions and cell migration. A key event in an immune response involves the migration of leukocytes to a disease site. During an inflammatory response, leukocytes are recruited to the site of injury and extravasated by a series of cellular interactions involving cell-cell and cell-substrate adhesion.
One family of molecules that serve an important adhesive function are integrins. Integrins are expressed on cell surfaces and function in cell-cell and cell-substrate adhesion. Integrins are alpha-beta heterodimers: each integrin has an alpha (xcex1) subunit non-covalently binded to a beta (xcex2) subunit. When activated, integrins bind to extracellular ligands and induce adhesion (the expression of integrins on a cell surface alone is inadequate for adhesionxe2x80x94they must be activated to become adhesive). The integrin activation state is transient, such that there is a rapid flux between adhesive and non-adhesive states which is important for cell movement, e.g., a cell is endowed with the ability to rapidly adhere to various cell surfaces and matrices and to migrate among cells and tissue.
There are four known integrins having a xcex22 or CD18 subunit which comprise the CD11/CD18 integrin sub-family, namely, Lymphocyte Function-associated Antigen 1 (LFA-1) (CD11a/CD18 or xcex1Lxcex22); Macrophage Antigen 1 (Mac-1) (CD11b/CD18 or xcex1Mxcex22); p150,95 (CD11c/CD18 or xcex1Xxcex22); and xcex1Dxcex22. The CD11/CD18 family of integrins are also referred to as Leukointegrins as they are expressed on the surface of various leukocyte cells, and they mediate a number of inflammation-related cellular interactions. See Diamond et al., xe2x80x9cThe Dynamic Regulation of Integrin Adhesiveness,xe2x80x9d Current Biology, Vol. 4 (1994) at pp. 506-532.
Ligands to LFA-1 and Mac-1 comprise the intercellular adhesion molecule (ICAM) ICAM-1. LFA-1, the primary CD11/CD18 integrin, also binds with ICAM-2 and ICAM-3. ICAMs are found on endothelium cells, leukocytes, and other cell types, and their interaction with CD11/CD18 integrins is critical to immune system function. The interaction between the CD18 integrins, particularly LFA-1, and ICAMs mediates antigen presentation, T-cell proliferation, and adhesion between the endothelium and activated leukocytes which is necessary for leukocytes to migrate from the circulatory system into tissue. A condition termed xe2x80x9cLeukocyte Adhesion Deficiencyxe2x80x9d has been identified in patients having a severe deficiency in CD18 integrins. These patients are unable to mount a normal inflammatory or immune response; they suffer from disorders such as recurrent infections, poor wound healing, granulocytosis, progressive periodontitis, and umbilical cord separation. See Anderson et al., xe2x80x9cLeukocyte LFA-1, OKMI, p150,95 Deficiency Syndrome: Functional and Biosynthesis Studies of Three Kindreds,xe2x80x9d Fed. Proc., Vol. 44 (1985), pp. 2671-2677.
While sufficient levels of CD18 integrins interacting with ICAMs are needed to mount a normal immune response, significant cellular and tissue injury can result in chronic inflammatory states where there is an inappropriate influx of leukocytes to the disease site. Continuous recruitment of leukocytes from blood vessels into inflamed tissue, as in chronic inflammatory states, can perpetuate tissue injury and lead to excessive fibrous repair and autoimmune disease. Thus, inhibition of the interaction between LFA-1 and/or Mac-1 and their ICAMs can be advantageous in treating inflammatory or immune disease. For example, monoclonal antibody blockade of either ICAM or LFA-1 has been shown to prevent the migration of leukocytes into tissue and the subsequent development of inflammatory disease in animal models of rheumatoid arthritis, inflammatory bowel disease, and pulmonary inflammation (e.g., asthma). Knockout mice deficient in ICAMs have reduced susceptibility to induced arthritis, ischemia injury, impaired lung inflammatory responses, and increased tolerance to transplantations (e.g. heart grafts). See Anderson, supra. Antibodies blocking the ICAM-LFA-1 interaction reportedly suppress cardiac allograft rejection and islet cell xenograft rejection in animal models. See Gorski, xe2x80x9cThe Role of Cell Adhesion Molecules in Immunopathology,xe2x80x9d Immunology Today, Vol. 15 (1994), at pp. 251-255.
Compounds inhibiting CD18 integrins, ICAMs, or the LFA-1:ICAM interaction could potentially demonstrate a wide range of utilities in treating inflammatory or immune diseases. Blocking LFA-1 reportedly inhibits the influx of leukocytes in almost every system, including the skin, peritoneum, synovium, lung, kidney and heart, and blocking ICAM-1 would be expected to have similar effects. Also, present therapies for many inflammatory or immune diseases have drawbacks. For example, current treatments for asthma include xcex22-agonists, inhaled corticosteroids, and LTD4 antagonists. However, xcex22-agonists have limited efficacy and inhaled corticosteroids raise safety concerns. To treat psoriasis, current therapies include PUVA, methotrexate, cyclosporin A, and topical treatments. The first three of those therapies raise toxicity issues over long-term (6-9 month) use, whereas topical treatments have limited efficacy. Additionally, these treatments typically are applied only in response to flares and not as a prophylaxis measure. There is a need for pharmaceuticals having increased effectiveness and fewer side effects.
Accordingly, there is interest in developing Leukointegrin or ICAM antibodies and antagonists of Leukointegrins and/or ICAMs. Thiadiazole-based compounds reportedly inhibit LFA-1 and Mac-1 binding with ICAM-1 and are claimed to be useful as anti-inflammatory agents. See Intern. Pub. No. WO 99/20,618, xe2x80x9cThiadiazole Amides Useful as Anti-Inflammatory Agentsxe2x80x9d filed by Pharmacia and Upjohn Co. (See also WO 99/20,617, also to Pharmacia and Upjohn.) Thiazole compounds linked to phenyl and pyrazole rings are claimed to be active LFA-1/ICAM inhibitors. Sanfilippo et al., xe2x80x9cNovel Thiazole Based Heterocycles as Inhibitors of LFA-1/ICAM-1 Mediated Cell Adhesion,xe2x80x9d J. Med. Chem. Vol. 38 (1995) at pp.1057-1059. A series of small molecules comprising 1-(3,5 dichlorophenyl) imidazolidines are claimed to be antagonists to the binding of ICAMs with CD18 integrins. See Intern. Pub. No. WO 98/39303, xe2x80x9cSmall Molecules Useful in the Treatment of Inflammatory Disease,xe2x80x9d filed by Boehringer Ingelheim Pharmaceuticals, Inc. (See also Boehringer patent applications WO 01/07052, WO 01/07048, WO 01/07044, WO 01/06984, and WO 01/07440). A series of compounds comprising various benzylamines and 2-bromobenzoyl-tryptophan are claimed to be antagonists to LFA-1/ICAM-1 receptor binding. See Intern. Pub. No. WO99/49,856, xe2x80x9cAntagonists for Treatment of CD11/CD18 Adhesion Receptor Mediated Disorders,xe2x80x9d filed by Genentech, Inc. See also Intern. Pub. No. WO 00/21,920, xe2x80x9cDiaminopropionic Acid Derivatives,xe2x80x9d filed by Hoffmann-La Roche Inc., disclosing a series of compounds claimed to block ICAM activity and have particular utility in treating reperfusion injury following acute myocardial infarction.
As may be appreciated, those in the field of pharmaceutical research continue to seek to develop new compounds and compositions for treating inflammatory or immune disease such as inhibitors of Leukointegrins and/or ICAMs. Particularly in the area of immune response, many individuals respond differently to different drugs. Thus, there is an interest in providing consumers not only with pharmaceutical compounds and compositions demonstrating increased effectiveness and reduced side-effects but also different structures or mechanisms of action to provide consumers with a choice of options. The instant invention is directed to hydantoin compounds that are effective as antagonists of Leukointegrins and/or ICAMs. Hydantoin compounds are disclosed in European patent application Serial No. 0 272 594 A2 to Hoechst Aktiengesellschaft for use as herbicides; in U.S. Pat. No. 5,605,877 to Schafer et al. for use as herbicides; and in European patent application Ser. No. EP 1 004 583 A2 and Intern. Pub. No. WO 98/58,947 both to Pfizer Inc., for use as intermediates in making growth hormone secretagogues. Hydantoin compounds are disclosed in Intern. Pub. No. WO 01/30781 A2 (published May 3, 2001) to Tanabe Seiyaku Co. Ltd, xe2x80x9cInhibitors of xcex1Lxcex22 Mediated Cell Adhesion.xe2x80x9d
Each of the patents, patent applications and publications referenced above and hereinafter is incorporated herein by reference.
The present invention provides compounds useful for treating inflammatory or immune disease having the formula (I): 
and pharmaceutically-acceptable salts thereof, in which:
L and K, taken independently, are O or S;
M is N or CH;
Y is CH or N;
Z is hydrogen, alkyl, or substituted alkyl, provided that Z may be selected from arylalkyl and heteroarylalkyl only when M is CH and/or when ring A has a second ring fused thereto;
T is nitrogen, CH, or a carbon atom substituted with an R3 group;
R1 is Q-aryl or Q-heteroaryl, wherein (a) when T is not nitrogen, Q is selected from a bond, xe2x80x94Oxe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(xe2x95x90O)xe2x80x94, xe2x80x94NR10C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)NR10xe2x80x94, xe2x80x94NR10CO2xe2x80x94, C1-4alkylene, C1-4substituted alkylene, C1-4alkenylene, C1-4substituted alkenylene, and optionally-substituted bivalent C1-4alkoxy, C1-4alkylthio, C1-4alkylamino, C1-4aminoalkyl, C0-4alkylsulfonyl, C0-4alkylsulfonamide, C1-4acyl, or C0-4alkoxycarbonyl, or when Z is arylalkyl or heteroarylalkyl, R1 may join with an R3 group to form a fused carbocyclic or heterocyclic ring; or (b) when T is nitrogen, then Q is selected from a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(xe2x95x90O)xe2x80x94, xe2x80x94C1-4alkylene, C1-4substituted alkylene, C1-4alkenylene, C1-4substituted alkenylene, or optionally-substituted bivalent C1-4alkoxy, C1-4alkylthio, C1-4aminoalkyl, C0-4alkylsulfonyl, C0-4alkylsulfonamide, C1-4acyl, or C1-4alkoxycarbonyl, provided that when M is N, T is N, r is 1, and s is 2 such that ring A is piperazine, R1 is not an amine-protecting group;
R3 is selected from at least one of (i) a substituent R3, wherein each substituent R3 is individually attached to any available carbon or nitrogen atom of ring A and at each occurrence is selected independently of each other R3 from halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, OR8, NR8R9, CO2R8, (Cxe2x95x90O)R8, C(xe2x95x90O)NR8R9, NR8C(xe2x95x90O)R9, NR8C(xe2x95x90O)OR9, OC(xe2x95x90O)R8, OC(xe2x95x90O)NR8R9, SR8, S(O)qR8a, NR8SO2R9, SO2NR8R9, aryl, heteroaryl, heterocyclo, and cycloalkyl, and when attached to an atom of ring A other than T, R3 is optionally keto (xe2x95x90O), provided that when R3 is attached to the atom designated as the C-5 atom of ring A, then R3 is not aryl or heteroaryl; and (ii) a first group R3 and a second group R3, wherein the first group R3 and the second group R3 are attached to two adjacent atoms of ring A and together form an optionally-substituted carbocyclic or heterocyclic ring fused to ring A;
R4a and R4b are selected independently of each other from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, hydroxy, alkoxy, substituted alkoxy, phenyloxy, benzyloxy, CO2H, C(xe2x95x90O)H, amino, alkylamino, substituted alkylamino, CO2alkyl, (Cxe2x95x90O)alkyl, and alkylthio;
R8 and R9 (i) selected independently of each other are hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclo; or (ii) taken together form a heterocyclo ring;
R8a is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo;
R10 is hydrogen, alkyl, or substituted alkyl;
n is 0, 1, or 2;
q is 1, 2, or 3;
r is 1 or 2; and
s is 0, 1, or 2.
The following are definitions of terms used in this specification and appended claims. The initial definition provided for a group or term herein applies to that group or term throughout the specification and claims, individually or as part of another group, unless otherwise indicated.
The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. Lower alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms, are most preferred. When numbers appear in a subscript after the symbol xe2x80x9cCxe2x80x9d, the subscript defines with more specificity the number of carbon atoms that a particular group may contain. For example, xe2x80x9cC1-6alkylxe2x80x9d refers to straight and branched chain alkyl groups with one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and so forth.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to an alkyl group as defined above having one, two, or three substituents selected from the group consisting of halo, alkenyl, alkynyl, nitro, cyano, amino, hydroxy, alkoxy, alkylthio, xe2x80x94NHSO2, xe2x80x94N(alkyl)SO2, xe2x80x94NHSO2(alkyl), xe2x80x94NHSO2(aryl), xe2x80x94N(alkyl)SO2(alkyl), xe2x80x94N(alkyl)SO2(aryl), xe2x80x94SO2(alkyl), xe2x80x94SO2(aryl), xe2x80x94SO2N(aryl)(alkyl), xe2x80x94SO2N(alkyl)2, xe2x80x94NH(alkyl), xe2x80x94NH(cycloalkyl), xe2x80x94N(alkyl)2, xe2x80x94CO2H, xe2x80x94C(xe2x95x90O)H, xe2x80x94CO2-alkyl, xe2x80x94(Cxe2x95x90O)alkyl, xe2x80x94(Cxe2x95x90O)NH2, xe2x80x94(Cxe2x95x90O)NH(alkyl), xe2x80x94(Cxe2x95x90O)NH(cycloalkyl), xe2x80x94(Cxe2x95x90O)N(alkyl)2, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2-alkyl, keto (xe2x95x90O), xe2x95x90Nxe2x80x94OH, xe2x95x90Nxe2x80x94O-alkyl, aryl, heteroaryl, heterocyclo, and cycloalkyl, including phenyl, benzyl, phenylethyl, phenyloxy, and phenylthio. When a substituted alkyl includes an aryl, heterocyclo, heteroaryl, or cycloalkyl substituent, said ringed systems are as defined below and thus may have zero, one, two, or three substituents, also as defined below.
The term xe2x80x9calkenylxe2x80x9d refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms and at least one double bond. Alkenyl groups of 2 to 6 carbon atoms and having one double bond are most preferred.
The term xe2x80x9calkynylxe2x80x9d refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms and at least one triple bond. Alkynyl groups of 2 to 6 carbon atoms and having one triple bond are most preferred.
The term xe2x80x9calkylenexe2x80x9d refers to bivalent straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, e.g., {xe2x80x94CH2xe2x80x94}n, wherein n is 1 to 12, preferably 1-8. Lower alkylene groups, that is, alkylene groups of 1 to 4 carbon atoms, are most preferred. The terms xe2x80x9calkenylenexe2x80x9d and xe2x80x9calkynylenexe2x80x9d refer to bivalent radicals of alkenyl and alknyl groups, respectively, as defined above.
The term xe2x80x9calkoxyxe2x80x9d refers to an alkyl group as defined above having a carbon atom replaced by one or more oxygen atoms. For example, the term xe2x80x9calkoxyxe2x80x9d includes the groups xe2x80x94Oxe2x80x94C1-12alkyl, xe2x80x94C1-6alkylene-Oxe2x80x94C1-6alkyl, and so forth.
The term xe2x80x9calkylthioxe2x80x9d refers to an alkyl group as defined above having a carbon atom replaced by one or more sulfur (xe2x80x94Sxe2x80x94) atoms. For example, the term xe2x80x9calkylthioxe2x80x9d includes the groups xe2x80x94Sxe2x80x94C1-12alkyl, xe2x80x94C1-6alkylene-Sxe2x80x94C1-6alkyl, etc.
The term xe2x80x9calkylaminoxe2x80x9d refers to an alkyl group as defined above bonded through one or more nitrogen atoms (e.g., xe2x80x94NRxe2x80x94 groups). For example, the term xe2x80x9calkylaminoxe2x80x9d includes the groups xe2x80x94NHxe2x80x94C1-12alkyl, xe2x80x94NHxe2x80x94C1-6alkylene-NHxe2x80x94C1-6alkyl, etc. The term alkylamino refers to straight and branched chain groups and thus, for example, includes the groups xe2x80x94NH(C1-12alkyl) and xe2x80x94N(C1-6alkyl)2. When a subscript is used with reference to an alkoxy, alkylthio or alkylamino, the subscript refers to the number of carbon atoms that the group may contain in addition to heteroatoms. Thus, for example, monovalent C1-2alkylamino includes the groups xe2x80x94NHxe2x80x94CH3, xe2x80x94NHxe2x80x94CH2xe2x80x94CH3, and xe2x80x94Nxe2x80x94(CH3)2.
When reference is made to a substituted alkoxy, substituted alkylthio, or substituted alkylamino group, the alkyl portion of the alkoxy, alkylthio and alkylamino groups may have one to three substituents selected from those recited above for substituted alkyl. The nitrogen atom of the alkylamino group may optionally be substituted with a group selected from alkyl, substituted alkyl, alkenyl, alkynyl, cyano, xe2x80x94SO2(alkyl), xe2x80x94SO2(aryl), xe2x80x94CO2H, xe2x80x94C(xe2x95x90O)H, xe2x80x94CO2-alkyl, xe2x80x94(Cxe2x95x90O)alkyl, aryl, heteroaryl, heterocyclo, and cycloalkyl.
The alkoxy, alkylthio, or alkylamino groups may be monovalent or bivalent. By xe2x80x9cmonovalentxe2x80x9d it is meant that the group has a valency (i.e., power to combine with another group), of one, and by xe2x80x9cbivalentxe2x80x9d it is meant that the group has a valency of two.
When the term xe2x80x9calkylxe2x80x9d is used as a suffix in conjunction with a second group, such as in xe2x80x9carylalkyl,xe2x80x9d xe2x80x9caminoalkyl,xe2x80x9d or xe2x80x9ccycloalkylalkylxe2x80x9d, it is meant that an alkyl group is used as a linker to the second group. Thus, for example, the term arylalkyl includes benzyl, phenylethyl, etc., and aminoalkyl includes the group xe2x80x94CH2xe2x80x94CH2xe2x80x94NH2. In such a case, the referenced second group (e.g., aryl in arylalkyl) is as defined herein and thus may be substituted as set forth in these definitions.
The term xe2x80x9chalogenxe2x80x9d includes chloro, bromo, fluoro, and iodo.
The term xe2x80x9chaloalkylxe2x80x9d means an alkyl having one or more halo substituents, e.g., including trifluoromethyl.
The term xe2x80x9chaloalkoxyxe2x80x9d means an alkoxy group having one or more halo substituents. For example, xe2x80x9chaloalkoxyxe2x80x9d includes xe2x80x94OCF3.
The term xe2x80x9cacylxe2x80x9d refers to a carbonyl group 
linked to an organic radical including an alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, or substituted alkynyl, as defined above. The organic radical to which the carbonyl group is attached may be monovalent (e.g., xe2x80x94C(xe2x95x90O)-alkyl), or bivalent (e.g., xe2x80x94C(xe2x95x90O)alkylene, etc.)
The term xe2x80x9calkoxycarbonylxe2x80x9d refers to a carboxy or ester group 
linked to an organic radical including an alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, or substituted alkynyl, as defined above. The organic radical to which the carboxy group is attached may be monovalent (e.g., xe2x80x94CO2-alkyl), or bivalent (e.g., xe2x80x94CO2-alkylene, etc.)
The term xe2x80x9ccarbamylxe2x80x9d refers to xe2x80x94NRxe2x80x2xe2x80x94C(xe2x95x90O)Rxe2x80x3 or xe2x80x94C(xe2x95x90O)NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 may be hydrogen, alkyl, substituted alkyl, or cycloalkyl, as defined above.
The term xe2x80x9csulfonylxe2x80x9d refers to a sulphoxide group (i.e., xe2x80x94S(O)1-2xe2x80x94) linked to an organic radical including an alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, or substituted alkynyl group, as defined above. The organic radical to which the sulphoxide group is attached may be monovalent (e.g., xe2x80x94SO2-alkyl), or bivalent (e.g., xe2x80x94SO2-alkylene, etc.)
The term xe2x80x9csulfonamidexe2x80x9d refers to the group xe2x80x94S(O)2NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 may be hydrogen or alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, or substituted alkynyl, as defined above. Rxe2x80x2 and Rxe2x80x3 may be monovalent or bivalent (e.g., xe2x80x94SO2xe2x80x94NH-alkylene, etc.)
The term xe2x80x9ccycloalkylxe2x80x9d refers to optionally-substituted fully saturated and partially unsaturated hydrocarbon rings of 3 to 9, preferably 3 to 7 carbon atoms. The term xe2x80x9ccycloalkylxe2x80x9d includes such rings having zero, one, two, or three substituents, preferably zero or one, selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, amino, hydroxy, alkoxy, alkylthio, xe2x80x94NHSO2, xe2x80x94N(alkyl)SO2, xe2x80x94NHSO2(alkyl), xe2x80x94NHSO2(aryl), xe2x80x94N(alkyl)SO2(alkyl), xe2x80x94N(alkyl)SO2(aryl), xe2x80x94SO2(alkyl), xe2x80x94SO2(aryl), xe2x80x94SO2N(aryl)(alkyl), xe2x80x94SO2N(alkyl)2, xe2x80x94NH(alkyl), xe2x80x94NH(cycloalkyl), xe2x80x94N(alkyl)2, xe2x80x94CO2H, xe2x80x94C(xe2x95x90O)H, xe2x80x94CO2-alkyl, xe2x80x94(Cxe2x95x90O)alkyl, xe2x80x94(Cxe2x95x90O)NH2, xe2x80x94(Cxe2x95x90O)NH(alkyl), xe2x80x94(Cxe2x95x90O)NH(cycloalkyl), xe2x80x94(Cxe2x95x90O)N(alkyl)2, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2xe2x80x94alkyl, keto, xe2x95x90Nxe2x80x94OH, xe2x95x90Nxe2x80x94O-alkyl, aryl, heteroaryl, heterocyclo, and a five or six membered ketal, i.e. 1,3-dioxolane or 1,3-dioxane. The term xe2x80x9ccycloalkylxe2x80x9d also includes such rings having a bridge of 3 to 4 carbon atoms.
The term xe2x80x9carylxe2x80x9d refers to phenyl, biphenyl, 1-naphthyl and 2-naphthyl, with phenyl being preferred. The term xe2x80x9carylxe2x80x9d includes such rings having from zero, one, two or three substituents selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, amino, hydroxy, alkoxy, alkylthio, xe2x80x94NHSO2, xe2x80x94N(alkyl)SO2, xe2x80x94NHSO2(alkyl), xe2x80x94NHSO2(aryl), xe2x80x94N(alkyl)SO2(alkyl), xe2x80x94N(alkyl)SO2(aryl), xe2x80x94SO2(alkyl), xe2x80x94SO2(aryl), xe2x80x94SO2N(aryl)(alkyl), xe2x80x94SO2N(alkyl)2, xe2x80x94NH(alkyl), xe2x80x94NH(cycloalkyl), xe2x80x94N(alkyl)2, xe2x80x94CO2H, xe2x80x94C(xe2x95x90O)H, xe2x80x94CO2-alkyl, xe2x80x94(Cxe2x95x90O)alkyl, xe2x80x94(Cxe2x95x90O)NH2, xe2x80x94(Cxe2x95x90O)NH(alkyl), xe2x80x94(Cxe2x95x90O)NH(cycloalkyl), xe2x80x94(Cxe2x95x90O)N(alkyl)2, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2-alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, cycloalkyl, heterocyclo, and heteroaryl.
When the term xe2x80x9carylxe2x80x9d is used with a hypen following another group, as in xe2x80x94Oxe2x80x94C0-2alkylene-aryl, xe2x80x94Sxe2x80x94C0-2alkylene-aryl, xe2x80x94Nxe2x80x94C0-2alkylene-aryl, acyl-aryl, alkoxy-carbonyl-aryl, or sulfonamide-aryl, it is meant that the hypenated group or groups serve as a linker to the aryl. In such a case, the aryl may be unsubstituted or substituted with one to three groups, as defined above.
The term xe2x80x9cheterocycloxe2x80x9d refers to substituted and unsubstituted non-aromatic 3 to 7 membered monocyclic groups, 7 to 11 membered bicyclic groups, and 10 to 15 membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings. Each ring of the heterocyclo group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The heterocyclo group may be attached at any available nitrogen or carbon atom. The heterocyclo ring may contain zero, one, two or three substituents selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, amino, hydroxy, alkoxy, alkylthio, xe2x80x94NHSO2, xe2x80x94N(alkyl)SO2, xe2x80x94NHSO2(alkyl), xe2x80x94NHSO2(aryl), xe2x80x94N(alkyl)SO2(alkyl), xe2x80x94N(alkyl)SO2(aryl), xe2x80x94SO2(alkyl), xe2x80x94SO2(aryl), xe2x80x94SO2N(aryl)(alkyl), xe2x80x94SO2N(alkyl)2, xe2x80x94NH(alkyl), xe2x80x94NH(cycloalkyl), xe2x80x94N(alkyl)2, xe2x80x94CO2H, xe2x80x94C(xe2x95x90O)H, xe2x80x94CO2-alkyl, xe2x80x94(Cxe2x95x90O)alkyl, xe2x80x94(Cxe2x95x90O)NH2, xe2x80x94(Cxe2x95x90O)NH(alkyl), xe2x80x94(Cxe2x95x90O)NH(cycloalkyl), xe2x80x94(Cxe2x95x90O)N(alkyl)2, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2-alkyl, aryl, heteroaryl, heterocyclo, cycloalkyl, keto, xe2x95x90Nxe2x80x94OH, xe2x95x90Nxe2x80x94O-alkyl, and a five or six membered ketal, i.e., 1,3-dioxolane or 1,3-dioxane.
Exemplary monocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like. Exemplary bicyclic heterocyclo groups include quinuclidinyl.
The term xe2x80x9cheteroarylxe2x80x9d refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. The aromatic portion of the heteroaryl ring system may contain zero, one, two or three substituents selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, amino, hydroxy, alkoxy, alkylthio, xe2x80x94NHSO2, xe2x80x94N(alkyl)SO2, xe2x80x94NHSO2(alkyl), xe2x80x94NHSO2(aryl), xe2x80x94N(alkyl)SO2(alkyl), xe2x80x94N(alkyl)SO2(aryl), xe2x80x94SO2(alkyl), xe2x80x94SO2(aryl), xe2x80x94SO2N(aryl)(alkyl), xe2x80x94SO2N(alkyl)2, xe2x80x94NH(alkyl), xe2x80x94NH(cycloalkyl), xe2x80x94N(alkyl)2, xe2x80x94CO2H, xe2x80x94C(xe2x95x90O)H, xe2x80x94CO2-alkyl, xe2x80x94(Cxe2x95x90O)alkyl, xe2x80x94(Cxe2x95x90O)NH2, xe2x80x94(Cxe2x95x90O)NH(alkyl), xe2x80x94(Cxe2x95x90O)NH(cycloalkyl), xe2x80x94(Cxe2x95x90O)N(alkyl)2, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2-alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, cycloalkyl, heterocyclo, and heteroaryl. The non-aromatic portion of the heteroaryl ring may contain one or more of the above-referenced substituents as well as keto (xe2x95x90O), xe2x95x90Nxe2x80x94OH, xe2x95x90Nxe2x80x94O-alkyl, and the like.
Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.
Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.
Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
The term xe2x80x9ccarbocyclicxe2x80x9d refers to optionally substituted aromatic or non-aromatic 3 to 7 membered monocyclic and 7 to 11 membered bicyclic groups, in which all atoms of the ring or rings are carbon atoms.
When the term xe2x80x9cunsaturatedxe2x80x9d is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.
Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds. Thus, for example, in compounds of formula (I), the substituent R3 may be attached to any available carbon atom of the xe2x80x9cAxe2x80x9d ring, including the atom T to which the group R1 is attached. For ease of reference, this atom may be referred to as the xe2x80x9cR1 substituted atom.xe2x80x9d When R1 comprises a heteroatom directly attached to ring A, advantageously any R3 group attached to T does not comprise a heteroatom directly attached to ring A, and vice-versa.
In compounds of formula (I), wherein R1 and/or R3 is attached to the 4-position atom of a piperazine ring (i.e., wherein M is N, A is a six-membered ring, and the fourth atom on the ring A [where M=atom 1] is a nitrogen atom), these groups preferably do not comprise xe2x80x9camine-protecting groups.xe2x80x9d More particularly, where ring A is 
R1 preferably is not an amine-protecting group. The term xe2x80x9camine-protecting groupxe2x80x9d as used herein refers to those groups that one skilled in the field would readily recognize as being suitable to protect the 4-position amine of a piperazinyl ring and which may be removed under typical deprotection conditions well known to those skilled in the field as set forth in Greene and Wuts, Protecting Groups in Organic Synthesis (John Wiley and Sons, New York 1991). For example, xe2x80x9camine-protecting groupxe2x80x9d includes those protecting groups disclosed in EP 1 004 583 A2, incorporated herein by reference, namely, Boc, CBZ, FMOC, benzyl, and ethyloxycarbonyl. The term xe2x80x9camine-protecting groupxe2x80x9d as used herein does not include xe2x80x94C2-4alkyl; xe2x80x94C1-4alkyl or C3-7cycloalkyl substituted with xe2x80x94CO2H, xe2x80x94SO2H, aryl, heteroaryl, or tetrazole, i.e., 
or C2-4alkyl substituted with alkoxy, N(alkyl)2, or heterocycle. The term xe2x80x9cend-product substituentxe2x80x9d means a substituent other than hydrogen that one skilled in the field would recognize is not an amine-protecting group as defined above. Thus, an xe2x80x9cend-product substituentxe2x80x9d includes xe2x80x94C2-4alkyl; xe2x80x94C1-4alkyl substituted with xe2x80x94CO2H, xe2x80x94SO2H, aryl, heteroaryl, or tetrazole; or C2-4alkyl substituted with alkoxy, N(alkyl)2, or heterocycle.
The compounds of formula (I) form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is understood to include reference to salts thereof. The term xe2x80x9csalt(s)xe2x80x9d denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, the term xe2x80x9csalt(s) may include zwitterions (inner salts), e.g., when a compound of formula (I) contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, e.g., in isolation or purification steps which may be employed during preparation, and thus, are contemplated within the scope of the invention. Salts of the compounds of the formula (I) may be formed, for example, by reacting a compound of the formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (for example, organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-xcex2-phenethylamine, 1-ephenamine, N,Nxe2x80x2-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Preferred salts include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate.
Prodrugs and solvates of the inventive compounds are also contemplated. The term xe2x80x9cprodrugxe2x80x9d denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula (I), and/or a salt and/or solvate thereof. For example, compounds containing a carboxy group can form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula (I) compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula (I) include C1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C1-6alkanoyloxy-C1-6alkyl, e.g. acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl, C1-6alkoxycarbonyloxy-C1-6alkyl, e.g. methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.
Compounds of the formula (I) and salts thereof may exist in their tautomeric form, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that the all tautomeric forms, insofar as they may exist, are included within the invention. Additionally, inventive compounds may have trans and cis isomers and may contain one or more chiral centers, therefore existing in enantiomeric and diastereomeric forms. The invention includes all such isomers, as well as mixtures of cis and trans isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers). When no specific mention is made of the configuration (cis, trans or R or S) of a compound (or of an asymmetric carbon), then any one of the isomers or a mixture of more than one isomer is intended. The processes for preparation can use racemates, enantiomers or diastereomers as starting materials. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization. The inventive compounds may be in the free or hydrate form.
Preferred compounds are those of formula (I) and/or pharmaceutically acceptable salts thereof: 
wherein
A is a saturated, 4 to 7-membered monocyclic cycloalkyl or heterocycle;
Y is CH;
M is N or CH;
L and K are O;
Z is alkyl or substituted alkyl except when M is N, Z is not arylalkyl or heteroarylalkyl;
either T is CH and R1 is xe2x80x94C0-2aekylene-aryl, xe2x80x94Oxe2x80x94C0-2alkylene-aryl, xe2x80x94Sxe2x80x94C0-2alkylene-aryl, xe2x80x94NR10xe2x80x94C0-2alkylene-aryl, acyl-aryl, oxy-carbonyl-aryl, or sulfonamide-aryl, or T is nitrogen and R1 is xe2x80x94C0-2alkylene-aryl, acyl-aryl, or alkoxycarbonyl-aryl;
R3 is alkyl, substituted alkyl, nitro, cyano, hydroxy, alkoxy, substituted alkoxy, amino, alkylamino, acyl, alkoxycarbonyl, carbamyl, sulfonyl, or sulfonamide;
R4a and R4b are each halogen;
R10 is hydrogen, alkyl, or substituted alkyl;
n is 0 or 1;
r is 1 or 2; and
s is 0, 1 or 2.
More preferred are compounds where n is 0 such that R3 is absent.
Advantageously, in compounds of formula (I), where A is piperazine and R1 is attached to the 4-position nitrogen atom of ring A (i.e., M is N, T is N, r is 1 and s is 2), R1 is preferably xe2x80x94C2alkylene-aryl; R1 is not an amine-protecting group and thus is not benzyl or Boc.
More preferred compounds are those having formula (I), above, in which
A is a saturated, 5 membered monocyclic ring (i.e., r and s are both 1);
M is N or CH;
L and K are both O;
Y is CH;
Z is hydrogen, lower alkyl, or lower alkyl substituted with hydroxy, lower alkoxy, or halogen,
T is CH and R1 is xe2x80x94C0-2alkylphenyl, xe2x80x94Oxe2x80x94C0-2alkylene-phenyl, xe2x80x94Sxe2x80x94C0-2alkylene-phenyl, xe2x80x94NR10xe2x80x94C0-2alkylene-phenyl, acyl-phenyl, oxycarbonyl-phenyl, or sulfonamide-phenyl, or T is N and R1 is xe2x80x94C0-2alkylene-phenyl, acyl-phenyl, or alkoxycarbonyl-phenyl, and said R1 phenyl group has zero or one substituent selected from halogen, C1-4alkyl, nitro, cyano, hydroxy, C1-4alkoxy, xe2x80x94CO2H, xe2x80x94C(xe2x95x90O)H, amino, and alkylamino; and
R4a and R4b are each chloro;
R10 is hydrogen or lower alkyl; and
n is 0 such that R3 is absent;
Most preferred compounds are (i) those having formula (Ia): 
in which
R1 is selected from 
(ii) those having the formula (Ib): 
in which R1 is selected from: 
wherein in each of the compounds of formula (Ia) and (Ib), R11 is selected from bromo, chloro, cyano, and methoxy, and R10 is selected from hydrogen and alkyl.
The compounds of the invention may be prepared by the exemplary processes described in the following reaction schemes A to J. Exemplary reagents and procedures for these reactions appear hereinafter. Starting materials are commercially available or can be readily prepared by one of ordinary skill in the art, and/or modifications can be made to the methods of Schemes A to J by one skilled in the art, using known methods. In the schemes, the groups R1, R3, K and Z are defined as recited in the claims. The group xe2x80x9cR2xe2x80x9d is used for ease of reference to describe the left-hand phenyl ring recited in the claims. Groups designated Rxe2x80x2, Rxe2x80x3, Z, Pxe2x80x2, and Pxe2x80x3 as well as solvents, temperatures, pressures, and other reaction conditions, may readily be selected as appropriate by one of ordinary skill in the art. 
In Scheme A, an amine of formula 1 is reacted with maleic anhydride 2, as described for example in Org. Synth. (1961), 41, 93-5, to yield maleimide 3. An amine 4 is reacted with chloromethyltrimethylsilane to give trimethylsilylmethylamine 5. This procedure can be conveniently carried out in acetonitrile or in an alcohol in the presence of a base such as TEA, potassium or sodium carbonate. Amine 5 is then condensed with formaldehyde in the presence of MeOH to give methoxymethylamine 6. The latter can be condensed with maleimide 3 under acidic catalysis to give tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione of formula (Ic). This reaction is carried out advantageously using a catalytic amount of TFA in DCM. 
In Scheme B, compound of formula (Ic) where R1 is a benzyl group can be debenzylated to give the N-unsubstituted molecule 7. Depending on the nature of the group R2, this step can be carried out through a catalytic hydrogenation over Pd/C in acetic acid or in alcohol, or by reaction with 1-chloroethyl chloroformate in DCM. Compound 7 can also be obtained by reaction of maleimide 3 with oxazolidinone 8 in refluxing toluene yielding 9 which is deprotected under acidic conditions, as described in Bull. Chem. Soc. Jpn. Vol. 60 (1987), at pp. 4079-89. Compound 9 can then be substituted by various electrophiles such as alkyl halides, alkyl mesylates or tosylates, acyl chlorides, or sulfonyl chlorides to yield the desired compounds of formula (Ic). This compound can also be obtained by reductive amination of 7 with a suitably functionalized aldehyde or ketone in the presence of a reducing agent such as sodium triacetoxyborohydride in DCM or sodium cyanoborohydride in acetonitrile. 
Substituted tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione of formula (Id) can be obtained as depicted in Scheme C. Thus reaction of maleimide 3 with an aminoacid 10 and an aldehyde 11 in a solvent such as acetonitrile gives 14. This transformation is described in J. Org. Chem. Vo. 53 (1988), pp. 1384-91, and Tetrahedron Vol. 44 (1988), at 1523-34. The nitrogen atom of 14 can then be substituted under classical conditions to give the desired compound of formula (Id). The same type of substitution pattern can also be obtained by the reaction of maleimide 3 with an aminoacide 12 and a ketone 13 in DMF at 100xc2x0 C. as described in Tetrahedron Lett. (1989), 30, at pp. 2841-44 or Bull. Chem. Soc. Jpn. (1987), 60, at pp. 4079-90. 
Tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione of formula (Ie) substituted by a carbonyl group can be obtained by reacting maleimide 3 with aziridine 15 in toluene or xylene (Scheme D), as described in J. Org. Chem. (1988), 53, 1882-7 or in Can. J. Chem. (1970), 48, 2215-26. 
Compounds having the formula (If) can be prepared as described in Scheme E. The monoprotected piperazine carboxylic acid ester 16 (see, e.g., Hu et al. Bioorg. Med. Chem. Lett. (1999), 9, at pp. 1121-6) is reacted with either an isocyanate or an isothiocyanate in a solvent such as methylene chloride or DMF in the presence of a base such as potassium carbonate, sodium carbonate or TEA, to yield the hydantoin 17. The protecting group is removed to yield 18, which can then be further substituted by reaction with an electrophile (alkylation, acylation, reaction with a sulfonyl chloride, etc.) or by reductive amination to yield the desired compound of formula (If) 
Protected hydroxy proline of formula 19 can be alkylated with Rxe2x80x2X in the presence of a base such as NaH in THF (as described for example in J. Med. Chem., [1988], 31(4), at pp. 875-885) or reacted with Rxe2x80x2OH under Mitsunobu conditions (as described for example in J. Med. Chem., [1988], 31(6), pp. 1148-1160) to give 20. Deprotection of 20 under acidic conditions yields 21, which is then cyclized with an isocyanate R2NCO or an isothiocyanate R2NCS in the presence of a base such as K2CO3 in a solvent such as DCM or DMF (as described for example in Eur. J. Med. Chem., (1996), 31, pp. 717-713) to yield compounds of formula (Ig). 
Protected hydroxy proline of formula 22 can be esterified with mesyl chloride then reacted with a thiol of formula Rxe2x80x2SH in the presence of a base such as NaH in THF (as described for example in J. Med. Chem. (1988), 31(4), at pp. 875-885) to give the thioether 24. Thioether 24 is deprotected under acidic conditions to give 25. Cyclization of 25 with an isocyanate R2NCO or an isothiocyanate R2NCS in the presence of a base such as K2CO3 in a solvent such as DCM or DMF gives compounds of formula (Ih). 
Hydroxy proline methyl ester of formula 26 can be cyclized with an isocyanate. R2NCO or an isothiocyanate R2NCS in the presence of a base such as K2CO3 in a solvent such as DCM or DMF to give 27. Compound 27 is oxidized in the presence of an oxidant such as pyridinium dichromate or Dess-Martin periodinane in DCM to give 29. Alternatively, oxo proline methyl ester of formula 28 (see for example, Bose, D. et al. Tetrahedron Lett.; 31; 47 [1990] at pp. 6903-6906) can be cyclized with an isocyanate R2NCO or an isothiocyanate R2NCS in the presence of a base such as K2CO3 in a solvent such as DCM or DMF to give the oxohydantoin 29. Reductive amination of 29 with an amine of formula 30 in the presence of a reducing agent such as sodium triacetoxyborohydride in DCM or sodium cyanoborohydride in acetonitrile under dehydrating conditions yields compounds of formula (Ii). 
Protected oxo proline methyl ester of formula 31 (see for example, Barralough, P., et al., Tetrahedron (1995), 51(14), at pp. 4195-4212) can be reacted with a Grignard Reagent Rxe2x80x2MgX (see for example, Tamaki M., et al., J. Org. Chem. (2001), 66, at pp. 3593-3596), to give 32. Compound 32 can be alkylated with Rxe2x80x3X in the presence of a base to give 33, which is deprotected to give 34. Cyclization of 34 with an isocyanate R2NCO or an isothiocyanate R2NCS in the presence of a base such as K2CO3 in a solvent such as DCM or DMF gives compounds of formula (Ij). 
Protected substituted proline of formula 20 (Scheme J) can be alkylated with Rxe2x80x2X in the presence of a base such as LDA or LIHMDS in THF (as described, for example, in Khalil, Ehab M. et al., J. Med. Chem.; [1999], 42(4), pp628-637) to give 35. After deprotection under acidic conditions, 36 is cyclized with an isocyanate R2NCO or an isothiocyanate R2NCS in the presence of a base such as K2CO3 in a solvent such as DCM or DMF (as described, for example, in Eur. J. Med. Chem., (1996), 31, pp. 717-713) to yield compounds of formula (1k).
Alternatively, monocyclic compounds such as 16 (Scheme K) can be substituted with Z groups other than hydrogen prior to cyclization, e.g., by treatment at low temperature (xe2x88x9278xc2x0 C.) in a solvent such as THF with a strong base such as LDA, potassium, lithium or sodium bis(trimethylsilyl)amide (KHMDS, LiHMDS, NaHMDS) to generate enolates which can be reacted with an electrophile ZX to give compounds having the desired Z groups.
The alkylation of other hydantoins to produce compounds of formula (Ik) or (Ikxe2x80x2) wherein Z is other than hydrogen can be performed as described in Scheme J and K, e.g., with an alkyl halide in the presence of base such as LDA or LiHMDS in THF. See also Seebach et al., J. Am Chem. Soc., Vol. 105(16) (1983) at pp. 5390-5398.
Each of the documents referenced above in the reactions schemes and hereinafter (e.g., in the Examples) is incorporated herein by reference.